PRODUCT INFORMATION Norditropin® SimpleXx® 5 mg, 10 mg

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PRODUCT INFORMATION Norditropin® SimpleXx® 5 mg, 10 mg
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PRODUCT INFORMATION
Norditropin® SimpleXx® 5 mg, 10 mg and 15 mg
Norditropin® FlexPro® 5 mg, 10 mg and 15 mg
NAME OF THE MEDICINE
Somatropin (rbe). Biosynthetic human growth hormone.
DESCRIPTION
Norditropin® (somatropin) is a polypeptide hormone of recombinant DNA origin. The
hormone is synthesized by a special strain of E coli bacteria that has been modified by the
addition of a plasmid which carries the gene for human growth hormone. Norditropin
contains the identical sequence of 191 amino acids constituting the naturally occurring
pituitary human growth hormone with a molecular weight of about 22,000 Daltons. ATC: H
01 AC 01.
1 mg of somatropin corresponds to 3 IU (International Units) of somatropin.
For excipients, see ‘Presentations and Storage Conditions.’
PHARMACOLOGY
Pharmacodynamics
Norditropin increases the growth rate in humans by stimulation of protein synthesis and other
metabolic processes.
Growth
The primary and most intensively studied action of somatropin is the stimulation of linear
growth. This effect is demonstrated in patients with somatropin deficiency.

Skeletal growth - the measurable increase in bone length after administration of
somatropin results from its effect on the cartilaginous growth areas of long bones.
Studies in vitro have shown that the incorporation of sulphate into proteoglycans is not
due to a direct effect of somatropin, but rather is mediated by the somatomedins or
insulin-like growth factors (IGF). The somatomedins, among them somatomedin-C
(otherwise known as IGF-1), are polypeptide hormones which are synthesised in the
liver, kidney and various other tissues. Somatomedin-C (IGF-1) is low in the serum of
hypopituitary dwarfs and hypophysectomised humans or animals, but its presence can be
demonstrated after treatment with somatropin.

Cell growth - it has been shown that the total number of skeletal muscle cells is markedly
decreased in short stature children lacking endogenous somatropin compared with
normal children, and that treatment with somatropin results in an increase in both the
number and size of muscle cells.

Organ growth - somatropin influences the size of internal organs, and it also increases
red cell mass.
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Protein metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and
growth are reflected by nitrogen retention which can be quantitated by observing the decline
in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin
therapy.
Carbohydrate metabolism
Somatropin has a diabetogenic effect. Hypopituitary children sometimes experience
hypoglycaemia, and acromegalic adults often suffer from diabetes mellitus. In healthy
subjects, very large doses of somatropin may impair glucose tolerance. Although the precise
mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking
the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually
increase as somatropin levels increase.
Fat metabolism
Growth hormone stimulates intracellular lipolysis, and administration of somatropin leads to
an increase in plasma free fatty acids, cholesterol and triglycerides. Untreated growth
hormone deficiency is associated with increased body fat stores including increased
subcutaneous adipose tissue. On somatropin replacement a general reduction of fat stores
and of subcutaneous tissue in particular, takes place.
Mineral metabolism
The retention of sodium is less than that of potassium. Serum levels of phosphate increase in
patients with growth hormone deficiency after somatropin therapy due to metabolic activity
associated with bone growth. Serum calcium levels are not altered. Although calcium
excretion in the urine is increased, there is a simultaneous increase in calcium absorption
from the intestine. Negative calcium balance, however, may occasionally occur during
somatropin treatment.
Connective tissue metabolism
Somatropin stimulates the synthesis of chondroitin sulphate and collagen as well as the
urinary excretion of hydroxyproline.
Pharmacokinetics
IV infusion of Norditropin SimpleXx® (33 ng/kg/min for 3 hours) to nine growth hormone
deficient patients, gave the following results: serum half-time of 21.1 ± 1.7 min, metabolic
clearance rate of 2.33 ± 0.58 mL/kg/min and a distribution space of 67.6 ± 14.6 mL/kg.
CLINICAL TRIALS
Bioequivalence of Norditropin® formulations
A randomised, single blind, 4 way cross over trial compared three Norditropin SimpleXx
formulations with Norditropin PenSet 24 in 28 healthy volunteers. Bioequivalence was
demonstrated between each of the Norditropin SimpleXx formulations and Norditropin
PenSet 24 after s.c. administration.
Turner Syndrome
There were two prospective, open label studies conducted to establish the efficacy of
Norditropin in girls with Turner Syndrome.
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GHTUR/BPD/6&12/NL was a prospective, randomised open label study in girls 11 years
(mean 13.6 years at study entry). All subjects received somatropin 6 IU/m2/day as either a
single daily dose or two divided doses until final height. All subjects received oestrogen to
induce puberty and later progesterone to induce withdrawal bleeds (although this may not be
optimal clinical practice, since there is evidence that treatment with gonadal steroids plus
somatropin may reduce the final height compared to treatment with somatropin alone).
Nineteen subjects were randomised with the mean duration of treatment of 43.1 months.
Seventeen reached final height, and two withdrew at close to final height. Final height was
defined by a height velocity <2 cm/year.
The baseline mean height (n=19) was 137.71 cm with a mean Karlberg standard deviation
score (SDS) of +0.663 and Roede SDS of -3.4. There was no difference in the effect on
growth of administering somatropin once or twice per day and the treatment groups were
pooled. The mean final height of the 17 subjects who reached final height was 155.08 cm
with a mean Karlberg SDS of +1.28 and Roede SDS of –2.13. If all subjects are included, the
mean final height is 155.2 cm. Height velocity increased compared to baseline.
Somatropin treated subjects remained shorter than girls without Turner syndrome but gained
on average 7.9 cm as a result of somatropin treatment (calculated according to Roede
standards).
GHTUR/BPD/5-13/NL is an ongoing prospective, open label multi-centre study comparing
three doses of somatropin (4, 6 and 8 IU/m2/day) in girls aged 2-11 years, combined with one
of two different dosing regimens of 17β-estradiol to induce puberty. 68 subjects are enrolled
with 13 at final height in January 1998, 14 withdrawn and 41 remaining in the study. By
April 1999, an additional 12 subjects had attained final height.
In January 1998, of the 14 withdrawn subjects, three had withdrawn due to adverse effects,
and the other 11 due to reaching near final height. Analysis of the 13 subjects who had
reached a mean final height of 159 ± 7.2 cm by January 1998 showed an average height gain
of 9.8 cm as a result of treatment with somatropin after a mean duration of treatment of 7.2 ±
0.69 years. The change from baseline score in the Karlberg and Roede SDS were +2.05 and
+1.58 respectively in these 13 subjects.
The two prospective Turner Syndrome studies included 85 patients in total. Seven patients
experienced peripheral oedema during the trials; however, a dose relationship was not shown.
One out of 17 patients in GHTUR/BPD/6&12/NL showed impaired glucose tolerance at more
than one assessment after three years of growth hormone treatment. In the dose-response
study, GHTUR/BPD/5-13/NL, no changes in glucose metabolism was detected; however, all
but one patient showed an increase in insulin AUC during the trial.
Chronic Renal Failure
Five studies (including some with sub-studies) were conducted to establish the efficacy of
Norditropin on growth in children with chronic renal failure (CRF) pre-transplant. One
multi-part study was conducted in children with CRF post-transplant. Two of the sub-studies
were prospective, double blind, placebo-controlled studies of the effect on growth of six
months of treatment with Norditropin 28 IU/m2/week in children with CRF pre-transplant
(GHCRF/BPD/1/NL Study 1) and post-transplant (the first year of GHCRF/BPD/2-5/NL in
pre-pubertal patients). The other studies were either dose-comparison studies (14 vs 28 or 32
and 28 vs 56 IU/m2/week for up to 30 months) or follow-up studies in patients continuing to
receive somatropin after previous participation in one of the placebo-controlled or dose
comparison studies. There are no final height data on children who began treatment prior to
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puberty and quality of life data are not available. Norditropin SimpleXx was not used in the
five studies, as all studies were initiated prior to its development.
GHCRF/BPD/1/NL (Study 1) and GHCRF/BPD/2-5/NL (first 12 months) were randomised,
double-blind, placebo-controlled studies on pre-pubertal children, involving 22 and 11
patients, respectively. In both studies, children were randomised to receive placebo or
Norditropin 28 IU/m2/week for 6 months, followed by the alternate treatment for 6 months.
Although final height data were not attained, both studies showed that there was a
significantly greater height velocity (equivalent of 9.8 vs 3 and 9.2 vs 3.75 cm/year,
respectively) and height velocity standard deviation score (5.9 vs 1.75 and 6.7 vs -0.6,
respectively) with Norditropin than placebo, indicating that six months treatment increased
height velocity. No longer-term placebo-controlled studies have been conducted.
The results of Norditropin treatment in children with CRF indicate that it resulted in shortterm increases in growth velocity, which diminished after the first 6-12 months. The safety
profile of Norditropin in post-transplant children is similar to that in the pre-transplant
setting; however, there is uncertainty about whether there is an increase in the frequency of
renal allograft rejection episodes in children with renal transplants who are treated with
somatropin. An increase in the incidence of rejection was seen in some trials but not in
others. The risk appeared greatest in children who had had a previous episode of rejection, in
whom immunosuppression was not maintained, or who received higher than the
recommended dose of somatropin.
Peripheral oedema was not reported during the five CRF studies. In three subjects (out of
124 patients randomised to the trials) OGTT were categorised as diabetic during the trial, of
which one diabetic response was assumed to be prednisone induced.
Small for Gestational Age (SGA)
There were three studies conducted to establish the efficacy of Norditropin in short children
born SGA mainly due to intrauterine growth retardation. The efficacy parameters did not
include quality of life measures as endpoints and were based on auxological criteria alone.
GHRETARD/BPD/14-20-21/NL (Study 1) is an ongoing multi-centre, double-blind,
randomised, two-arm study comparing two doses of somatropin (3 or 6 IU/m2/day (0.033 or
0.067 mg/kg/day)) for up to nine years. In the original study (14/NL), 79 short children born
with IUGR without catch-up growth were included; 78 children completed two years and
continued in the extension trial (20/NL) for a further two years. A total of 75 children
completed four years and entered the second extension of the trial (21/NL), and somatropin
treatment was continued at the same dose until final height. By August 2001, 18 children
completed the study, 37 were still ongoing, and 24 were withdrawn (18 withdrawn due to
attaining satisfactory height) during the nine-year trial period.
During the first year of therapy, height velocity (HV) increased from a mean of 5.6 cm/year
to 10.0 cm/year in the low-dose group and from 5.4 cm/year to 11.7 cm/year in the high-dose
group. HV subsequently decreased with time, but remained higher than pre-treatment HV up
to seven years. The difference in HV between the two dose groups was statistically
significant at Years 1 and 2. Results of other efficacy variables indicated a substantial effect
on linear growth resulting in a mean change in Roede SDS from -3.1 to -0.6 and from -3.1 to
-0.1 in the two dose-groups, respectively, after eight years of somatropin treatment. Longterm treatment (up to 9 years) was safe and well tolerated, and there were no withdrawals due
to serious adverse events.
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GHRETARD/BPD/16-20/NL (Study 2) was a single centre, open label study, in which 11 (8
females and 3 males) children (who failed to meet the inclusion criteria for inclusion in
14/NL due to age and/or puberty) were included. Trial conduct in 16/NL was the same as
that for 14/NL with the exception that all children received somatropin at a dose of 6
IU/m2/day. After two years of treatment, these children were allowed to continue in 20/NL
for a further two years. After a total of four years, children, who had not reached final height,
continued treatment in 21/NL at the same dose of somatropin until final height was reached.
Of the 11 children, nine completed the study (four reaching final height, and five reaching
near final height).
Data on the first four years of treatment were analysed; final height data on children in this
study were pooled with 21/NL and reported separately (see table below). Overall, there was
an increase in HV from pre-treatment to Year 1. HV then declined yearly primarily due to
the fact that subjects were nearing final height. Height standard deviation score (HSDS)
increased from a mean of -2.62 at baseline to -1.85 at Year 4.
Data on final height (defined by a height velocity <1 cm/year) are available on 40 subjects in
Studies 1 and 2. Of the subjects (26 males and 14 females) analysed, 10 subjects were GHD
and 30 (20 males and 10 females) were non-GHD, including 11 subjects (7 males and 4
females) with a baseline height < -3 SD. Mean final height data are shown in the following
table.
Baseline
Height
< -2 SD
(GHD +
non-GHD)
< -2 SD
(non-GHD)
< -3 SD
(non-GHD)
Male
Female
3 IU/m2/day
6 IU/m2/day
3 IU/m2/day
6 IU/m2/day
(0.033mg/kg/day) (0.067mg/kg/day) (0.033mg/kg/day) (0.067mg/kg/day)
168.3 ± 6.5
172.1 ± 6.5
160.8 ± 3.7
158.7 ± 4.8
(n = 13)
(n = 13)
(n = 5)
(n = 9)
168.5 ± 5.9
(n = 10)
164.6 ± 4.9
(n = 5)
171.5 ± 6.1
(n = 10)
172.9 ± 4.0
(n = 2)
160.9 ± 5.5
(n = 2)
(n = 0)
158.5 ± 5.1
(n = 8)
155.4 ± 4.6
(n = 4)
GHRETARD/F/1/F (Study 3) was a prospective, randomised, open label, parallel group,
multi-centre study comparing three regimens of somatropin for two years. Patients were
randomised to one of three treatment groups: 0.2 IU/kg/day (six days/week) continuous
treatment; 0.2 IU/kg/day (six days/week) non-continuous treatment (alternating periods of six
months treatment and non-treatment); and 0.4 IU/kg/day (six days/week) non-continuous
treatment (alternating periods of six months treatment and non-treatment). Of the 139
children randomised and allocated to the three treatment groups (46, 47, and 46,
respectively), 133 completed the study.
A dramatic change in HV from approximately 4.8 cm/year to 10 cm/year was found in all
treatment groups during the first six months of the study. Continuous treatment with 1.2
IU/kg/week resulted in the most beneficial growth in comparison to the alternating treatment
regimens. Except for during off-treatment periods, all regimens resulted in increased HV
and height gain during childhood. The alternating 2.4 IU/kg/week regimen did not appear to
be more efficient than the alternating 1.2 IU/kg/week regimen. There was a statistically
significant difference (p<0.001) in HSDS between the treatment groups, showing an increase
of 1.42 from -3.19, of 0.86 from -3.06, and of 1.02 from -3.11 in the three groups,
respectively.
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Deficiency in Adults
Clinical data are available on seven placebo-controlled studies and uncontrolled extensions
from four of these studies. The placebo-controlled studies range in duration from 4 to 12
months involving a total of 420 subjects (222 and 198 subjects in the somatropin and placebo
arms, respectively, equivalent to 94 patient years (somatropin treatment) and 84 patient years
(placebo treatment)). Two thirds of the subjects had Adult Onset [AO] growth hormone
insufficiency. Results, available on 203 subjects from 3 of the 4 studies which used the
insulin tolerance test to diagnose GH deficiency, showed 71% of subjects had a peak growth
hormone concentration of less than 2.5ng/mL. Primary outcomes commonly measured
across the studies included the efficacy and safety of Norditropin on body composition,
muscle strength, exercise capacity, and bone metabolism. Secondary outcomes included the
effects of Norditropin on lipid metabolism, thyroid metabolism, pituitary, adrenal and
gonadal function, cellular and humoral immune function and quality of life. Overall, the
studies demonstrated progressive improvement and partial normalisation of some surrogate
outcome parameters measured in those patients administered somatropin. Outcomes
statistically significantly improved by the end of twelve months as compared to placebo
included: body composition [total body fat, skinfold thickness, total body fat, total body lean
mass, waist/hip ratio]; bone metabolism [increased osteocalcin]; mineral metabolism
[increased alkaline phosphatase]; and thyroid metabolism [increased serum free T3]. Trial
analyses were undertaken in accordance with approved study protocols and subsequent
amendments. Due to unknown correlations between the assessments and dependencies
between hypotheses on primary efficacy and safety outcomes, adjustment for multiple
comparisons was not carried out.
Uncontrolled extension data are available from four of the seven studies. Involving over 182
subjects and ranging in duration from 16 months to five years [83 subjects ≥ 2 years, 40
subjects ≥ 4 years], these demonstrated overall that some of the modifications seen in the
shorter term, placebo-controlled studies continued to show progressive change (relative to
baseline) and approach values close to normal individuals at three years. The long-term
clinical significance of these changes is not clear. By three years, adults on somatropin
replacement show normalisation/progressive improvement in the following outcomes: body
composition [lean body mass to fat ratio]; bone metabolism [lumbal spine BMC, osteocalcin,
whole body BMC]; thyroid metabolism [increased serum free T3]; lipid metabolism [LDL,
HDL, cholesterol] and cardiac status [resting systolic/diastolic BP levels]. Following four
years of somatropin replacement, sustained change was shown with the following outcomes:
body composition [muscle volume and mass, body weight, total body fat, waist/hip ratio];
bone metabolism [lumbal spine BMD, osteocalcin, hydroxyproline]; thyroid metabolism
[increased serum free T3]; and cardiac status [systolic/diastolic BP levels]. There was no
statistically significant improvement in quality of life measurements; however, the changes
were consistent and in a direction denoting improvement.
The somatropin-related adverse effects observed in the studies were mild to moderate and
reversible with the most frequent side effects arising from the salt and water retaining effects
of the hormone manifesting mainly as fluid retention. These symptoms occurred in the early
weeks of treatment and improved or disappeared with dosage reduction.
Overall, the studies demonstrated that somatropin replacement leads to a correction of the
abnormalities in body composition caused by untreated growth hormone deficiency. The
long-term studies not only showed that the early changes are maintained, but also that some
endpoints continue to improve beyond twelve months of somatropin replacement. This
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observation demonstrates that several of the actions of somatropin on body structure and
function occur slowly and may take several years to normalise.
INDICATIONS
Children
Treatment of growth failure in children due to pituitary growth hormone deficiency.
Treatment of growth failure in girls due to gonadal dysgenesis (Turner Syndrome).
Treatment of growth failure in children due to chronic renal insufficiency whose height is on
or less than the twenty-fifth percentile and whose growth velocity is on or less than the
twenty-fifth percentile for bone age. Chronic renal insufficiency is defined as a glomerular
filtration rate of < 30 mL/min/1.73 m2.
Treatment of severe growth failure due to intrauterine growth retardation (i.e., children born
small for gestational age (birth weight and/or length < -2 SD) without spontaneous catch up
growth by 2 years of age).
Adults
Treatment of adults with severe growth hormone deficiency as diagnosed in the insulin
tolerance test for growth hormone deficiency and defined by peak growth hormone
concentrations of less than 2.5 nanogram/mL.
In order to establish Childhood Onset [CO] growth hormone insufficiency, reconfirmation by
one provocative test is recommended.
In order to establish isolated growth hormone deficiency two provocative tests are
recommended. In adults, the insulin tolerance test is the provocative test of choice. When the
insulin tolerance test is contraindicated, alternative provocative tests must be used. The
combined arginine or the glucagon test may also be considered; however these tests have less
established diagnostic value than the insulin tolerance test.
CONTRAINDICATIONS
Norditropin should not be used in children with closed epiphyses; in patients with retarded
growth due to any other cause than pituitary growth hormone deficiency unless specifically
indicated (see INDICATIONS); or in patients with a known hypersensitivity to any of the
ingredients.
Norditropin should not be used in patients with any evidence of active malignant tumours.
Intracranial neoplasm must be inactive and anti-tumour therapy must be completed prior to
instituting Norditropin therapy. Treatment with Norditropin should be discontinued if there
is any evidence of recurrent tumour growth.
Growth hormone is contraindicated in patients with proliferative or preproliferative diabetic
retinopathy.
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Growth hormone is contraindicated in those patients with Prader-Willi syndrome who would
otherwise qualify for Somatropin therapy (see INDICATIONS) who are severely obese or
have respiratory impairment.
In children with chronic renal disease, Norditropin treatment after renal transplantation
should not be initiated if the child has a history of more than one acute rejection episode or if
the time since transplantation is less than 12 months. In addition to this Norditropin treatment
should be discontinued in case of a new acute rejection episode.
Norditropin should not be initiated to treat patients with acute critical illness due to
complications following open heart surgery or abdominal surgery, multiple accident trauma
or to patients having acute respiratory failure (see PRECAUTIONS).
PRECAUTIONS
Treatment with Norditropin should be directed by specialists experienced in the diagnosis and
management of growth hormone deficiency. This is true also for the management of Turner
syndrome, chronic renal disease and SGA.
The maximum recommended daily dose should not be exceeded (see ‘Dosage and
Administration.’)
The stimulation of longitudinal growth in children can only be expected until the epiphysial
discs are closed. Slipped capital femoral epiphysis may occur more frequently in patients
with endocrine disorders and Legg-Calvé-Perthes disease may occur more frequently in
patients with short stature. These diseases may present as the development of a limp or
complaints of hip or knee pain and physicians should be alerted to this possibility.
The dosage in children with chronic renal disease is individual and must be adjusted
according to the individual response to therapy. The growth disturbance should be clearly
established before Norditropin treatment by following growth on optimal treatment for renal
disease over one year. Conservative management of uraemia with customary medication and
if needed dialysis should be maintained during Norditropin therapy.
Patients with chronic renal disease normally experience a decline in renal function as part of
the natural course of their illness. However, as part of the clinical management of the patient
during somatropin treatment, renal function should be monitored for excessive decline,
including signs of rejection episodes in transplanted patients. Particular caution should be
exercised if somatropin is used in children who have had a previous episode of rejection or in
whom immunosuppression is not assured (see ‘Clinical Trials’).
Patients with chronic renal disease may develop hyperparathyroidism which should be treated
appropriately before initiation of Norditropin therapy.
The dosage in children with intrauterine growth retardation is individual and must be adjusted
according to the individual response to therapy. Norditropin treatment is not indicated for
idiopathic short stature or familial short stature.
Norditropin contains the excipient poloxamer 188, which acts as a surfactant. Poloxamer 188
is excreted predominantly in the urine and its exposure is inversely proportional to
glomerular filtration rate. High s.c. doses of poloxamer 188, approximately 650 times the
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maximal expected clinical exposure based on body surface area, have been shown to induce
vacuolation of the renal tubules in rats. The findings from some clinical trials of poloxamer
188 have demonstrated that similar extremely high i.v. dosages of poloxamer 188 cause a
reversible acute renal dysfunction (i.e. decreased creatinine clearance observed).
Serum thyroxine levels may fall during treatment with Norditropin due to the increased
peripheral deiodination of T4 to T3.
Hypothyroidism may develop in patients with pituitary disease. As hypothyroidism interferes
with the response to Norditropin therapy patients should have periodic thyroid function tests
and thyroid hormone should be substituted when indicated. Patients with Turner syndrome
have an increased risk of developing primary hypothyroidism associated with anti-thyroid
antibodies.
Monitoring of growth of hands and feet in Turner syndrome patients treated with growth
hormone is recommended and a dose reduction to the lower part of the dose range should be
considered if increased growth is observed. Girls with Turner syndrome generally have an
increased risk of otitis media, and careful otological evaluation is recommended.
Treatment in growth hormone deficient adults should be attempted only after definitive
treatment of pituitary tumour (if present) is completed and all other pituitary hormone
deficiencies are corrected, as clinically indicated.
Patients with growth hormone deficiency secondary to an intracranial lesion should be
examined frequently for progression or recurrence of the underlying disease process.
Experience in patients older than 60 years and in patients with more than 10 years’ of
treatment in adult growth hormone deficiency is still limited.
Somatropin has been found to influence carbohydrate metabolism, therefore, patients should
be observed for evidence of glucose intolerance. Regular urine testing for evidence of
glycosuria should be carried out in all patients. In insulin treated patients, adjustment of
insulin dose may be needed after initiation of Norditropin treatment.
In SGA children it is recommended that fasting insulin and blood glucose be measured before
start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus
(e.g. familial history of diabetes, obesity, Turner syndrome, severe insulin resistance,
acanthosis nigricans), oral glucose tolerance testing (OGTT) should be performed. If overt
diabetes occurs, growth hormone should not be administered.
In SGA children it is recommended that the IGF-1 level be measured before start of treatment
and twice a year thereafter. If on repeated measurements IGF-1 levels exceed +2 SD
compared to references for age and pubertal status, the IGF-1 / IGFBP-3 ratio could be taken
into account to consider dose adjustment.
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be
monitored during treatment.
Leukaemia has been reported in a small number of growth hormone deficient patients some
of whom have been treated with somatropin. Based on current evidence it is unlikely that
somatropin is responsible for this. In patients in complete remission from tumours or
malignant disease, growth hormone therapy has not been associated with an increased relapse
rate. Nevertheless, patients who have achieved complete remission of malignant disease
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should be followed closely for relapse after commencement of Norditropin therapy.
Very rare cases of benign intracranial hypertension have been reported. If appropriate,
somatropin treatment should be discontinued. In cases of severe or recurrent headache, visual
symptoms, nausea and/or vomiting, a fundoscopy for papilloedema is recommended. If
papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be
considered and if, appropriate, growth hormone treatment should be discontinued. At present
there is insufficient evidence to guide clinical decision making in patients with resolved
intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for
symptoms of intracranial hypertension is necessary.
Two placebo-controlled clinical trials of patients in intensive care units treated with
somatropin in high doses (5.3-8 mg/day) have demonstrated an increased mortality among
patients suffering from acute critical illness due to complications following open heart or
abdominal surgery, multiple accidental trauma or acute respiratory failure. The safety of
continuing growth hormone in patients receiving replacement doses for approved indications
who concurrently develop these illnesses has not been established. Therefore, the potential
benefit of treatment continuation with growth hormone in patients having acute critical
illnesses should be weighed against the potential risk.
If injected subcutaneously, the injection site should be rotated to minimise the risk of
lipoatrophy.
Norditropin is not expected to affect the ability to drive or use machinery.
Carcinogenicity
Somatropin raises the serum levels of IGF-1. Associations between elevated serum IGF-1
concentrations and risk of certain cancers have been reported in epidemiological studies.
Causality has not been demonstrated. The clinical significance of these associations,
especially for subjects treated with somatropin who do not have growth hormone deficiency
and who are treated for prolonged periods, is not known.
Genotoxicity
There was no evidence of Norditropin-induced genotoxicity in assays for gene mutation in
bacteria or chromosomal damage in mouse bone marrow cells in vivo.
Effects on fertility
In a fertility study, female rats were treated s.c. with Norditropin for 2 weeks prior to mating
and for the first 7 days of pregnancy. Pregnancy rate was reduced at doses  1 IU/kg/day
(equivalent to 2 mg/m2/day, approximately 1.4 times the maximum clinical dose on a body
surface area basis) and resorption rate was increased at 3.3 IU/kg/day. However, litter size
was increased due to an increased number of released ova. In studies with other recombinant
human growth hormone preparations, increased incidences of irregular oestrous cycles and
delayed mating time were observed in rats treated with somatropin at s.c. doses of
0.1 IU/kg/day (equivalent to 0.2 mg/m2/day, about 15% of the maximum clinical dose on a
body surface area basis) or greater.
Use in Pregnancy (Category B1)
Animal reproduction studies have not been conducted with Norditropin. It is not known
whether Norditropin can cause fetal harm when administered to a pregnant woman or can
affect reproductive capacity. Another form of recombinant human growth hormone was not
teratogenic in rats or rabbits at respective doses of up to 15 and 28 times the maximum
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recommended clinical dose based on body surface area. In rats, recombinant human growth
hormone administered from late gestation to weaning, at 15 times the clinical dose based on
body surface area, was associated with increased body weight of pups at birth and
postnatally. Because animal reproductive studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
Use in Lactation
There have been no studies conducted with Norditropin in nursing mothers and it is not
known whether Norditropin is excreted in breast milk. It is unlikely that the intact growth
hormone would be excreted in the milk; however, following subcutaneous administration of
radiolabelled recombinant human growth hormone to lactating rats, radioactivity was
transferred to milk reaching four times the concentration found in maternal plasma.
Absorption of any intact protein in the gastrointestinal tract of the infant is extremely
unlikely.
Incompatibilities
In the absence of compatibility studies, the medicinal product must not be mixed with other
medicinal products.
INTERACTIONS WITH OTHER MEDICINES
Concomitant glucocorticoid therapy may inhibit growth and thereby oppose the growth
promoting effect of Norditropin. The effect of growth hormone on final height can also be
influenced by additional therapy with other hormones, e.g. gonadotrophin, anabolic steroids,
oestrogen and thyroid hormone. Concomitant administration with gonadal steroids may not
be optimal clinical practice, since there is evidence that treatment with gonadal steroids plus
somatropin may reduce the final height compared to treatment with somatropin alone.
Data from an interaction study performed in growth hormone deficient adults, suggests that
somatropin administration may increase the clearance of compounds known to be
metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by
cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine)
may be especially increased resulting in lower plasma levels of these compounds. The
clinical significance of this is unknown.
ADVERSE EFFECTS
When treatment with somatropin is initiated, fluid retention with peripheral oedema may
occur, especially in adults.
Carpal tunnel syndrome is common in adults. The symptoms are usually transient, dose
dependant and may require transient dose reduction.
Adverse reactions in children are uncommon or rare.
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Clinical trial experience
System organ class
Very common
> 1/10
Common
> 1/100; < 1/10
Metabolism and
nutrition disorder
Nervous system
disorder
In adults:
headache and
paraesthesia/
abnormal
sensation
Skin and
subcutaneous tissue
disorder
Musculoskeletal,
connective tissue
and bone disorder
General disorders
and administration
site conditions
Gastrointestinal
disorders
In adults:
peripheral oedema
(Please see text
above)
In adults:
arthralgia, joint
stiffness and
myalgia/skeletal
pain/stiffness,
carpal tunnel
syndrome
In adults:
injection site
reaction
Uncommon
> 1/1000; < 1/100
In adults: Diabetes
mellitus type 2
(Please see Post
marketing
experience)
In children: benign
intracranial
hypertension,
headache, seizure,
motor problems
In adults: pruritus
In children: skin
rash, transient local
skin reactions at the
injection site;
lipoatrophy
In adults: muscle
stiffness
In children:
arthralgia, slipped
epiphysis, scoliosis/
kyphoscoliois
Rare
> 1/10000; <1/1000
In children: allergy,
alopecia
In children: myalgia
In adults and
children: injection
site pain. In
children: injection
site reaction,
oedema
In children: nausea
In children with Turner syndrome increased growth of hands and feet has been reported
during growth hormone therapy.
Post marketing experience
Rare (less than 1 in 1000) cases of generalised hypersensitivity reactions (e.g. anaphylactic
reactions) have been reported. See ‘Contraindications.’
In addition to the above mentioned adverse drug reactions, those presented below have been
spontaneously reported and are by an overall judgement considered possibly related to
Norditropin treatment.
Slipped capital femoral epiphysis and Legg-Calvé-Perthes disease have been reported in
children treated with somatropin.
There have been reports of fatalities after initiating therapy with growth hormone in
paediatric patients with Prader-Willi syndrome, for which Norditropin is not approved, who
had one or more of the following risk factors: severe obesity, history of upper airway
obstruction or sleep apnoea, or unidentified respiratory infection. Male patients with one or
more of these factors may be at greater risk than females. Patients with Prader-Willi
syndrome should be evaluated for signs of upper airway obstruction and sleep apnoea before
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initiation of treatment with growth hormone. If pathological findings are observed during the
assessment of upper airway obstruction, the patient should be referred to an ear, nose, throat
specialist for treatment and resolution of the respiratory disorder before initiating somatropin
treatment. The patient should be monitored if sleep apnoea is suspected. If during treatment
with growth hormone, patients show signs of upper airway obstruction (including onset of or
increased snoring) and/or new onset sleep apnoea, treatment should be discontinued and a
new ear, nose, throat assessment should be performed. All patients with Prader-Willi
syndrome treated with growth hormone should also have effective weight control and be
monitored for signs of respiratory infection.
The following table lists further conditions reported in post-marketing experience.
Observation
CIOMS Frequency
Notes
Formation
of Rare:
>
antibodies directed <1/1000
against somatropin
1/10,000; The titres and binding capacities of these antibodies
have been very low and have not interfered with the
growth response to Norditropin administration.
Antibodies have potential for inhibition of further
linear growth response to continued somatropin
treatment. Patients failing to respond to treatment
should therefore be tested for antibodies.
Decrease in serum Very Rare: <1/10,000
thyroxin
levels
during Norditropin
therapy
(see
‘Precautions’).
Increase in blood Very rare <1/10,000
alkaline
phosphatase level
may be seen during
the treatment with
Norditropin.
benign intracranial Very Rare: <1/10,000
hypertension
Most of the available literature does not demonstrate
Diabetes mellitus Very Rare: <1/10,000
an increased incidence of diabetes associated with
type 2 cases have
somatropin treatment.
been reported
DOSAGE AND ADMINISTRATION
Treatment of Norditropin should be directed by specialists experienced in the diagnosis and
management of growth hormone deficiency. This is also true for the management of Turner
syndrome, chronic renal disease and SGA. The dosage must be individualised for each
patient in accordance with the individual’s response to therapy. Dosages can be calculated
according to body weight or body surface area.
Generally, daily subcutaneous administration in the evening, 6-7 days per week, is
recommended. Rotation of the injection site is recommended to minimise the risk of
lipoatrophy. Specific activity for somatropin: 1 mg = 3 International Units (IU).
Paediatric
Recommended dosages for children with growth hormone deficiency:
25-35 g/kg/day
Equal to: 0.7 – 1.0 mg/m2/day
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Recommended dosages for Turner Syndrome and Chronic Renal Disease:
50 g/kg/day
Equal to: 1.4 mg/m2/day
Recommended dosages for Small for Gestational Age (SGA):
33-67 g/kg/day
Equal to: 1-2 mg/m2/day
The dosage must be adjusted to the need of the individual patient. It is recommended to start
treatment with 33µg/kg/day. If catch-up growth has not commenced after 6 months of
observation (and verification of compliance by increase in IGF1 and/or IGFBP3) then the
physician may increase the dose up to 67µg/kg/day according to the patient’s needs.
It is recommended that the treating physician advise the parents/guardians that their children
are not being treated for growth hormone deficiency, and that treatment with Norditropin
induces catch-up growth during childhood and increases adult height. It is also recommended
that parents/guardians be advised that long term treatment with somatropin has been
associated with impaired glucose tolerance and malignancies. However, causality has not
been established and there is no evidence that somatropin treatment is associated with an
increased incidence of persistent impaired glucose tolerance or malignancies.
Adults
Recommended dosages for adults with growth hormone deficiency:
The dosage must be adjusted to the need of the individual patient. It is recommended to start
treatment with a low dose of 0.15-0.3 mg/day and to increase the dosage gradually at monthly
intervals based on clinical response. Serum insulin-like growth factor 1 (IGF-1) can be used
to guide dose titration.
Dose requirements decline with age. Maintenance dosages vary from patient to patient, but
seldom exceeds 1.0 mg.
Instructions for use and handling
Patients should be reminded to wash their hands thoroughly with soap and water and/or
disinfectant prior to any contact with Norditropin SimpleXx/FlexPro.
Do not use Norditropin SimpleXx/FlexPro if it does not appear water-clear and colourless.
(FlexPro only:) check this by turning the pen upside down once or twice.
Norditropin should not be shaken vigorously at any time.
Norditropin® SimpleXx®
 Norditropin SimpleXx cartridges MUST be used with the matching colour coded
NordiPen® to give the correct dose:
 Norditropin SimpleXx 5 mg (yellow) MUST be used with NordiPen 5 mg (yellow).
 Norditropin SimpleXx 10 mg (blue) MUST be used with NordiPen 10 mg (blue).
 Norditropin SimpleXx 15 mg (green) MUST be used with NordiPen 15 mg (green).
 Detailed instructions for use are included in the package insert (Consumer Medicine
Information) and NordiPen Instruction Manual. Patients should be advised to read these
instructions very carefully.
 The product is for multiple use in one patient only.
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Norditropin® FlexPro®
 Norditropin FlexPro is a pre-filled pen designed to be used with NovoFine needles (8
mm 30 G or smaller).
 Detailed instructions for use are included in the package insert (Consumer Medicine
Information). Patients should be advised to read these instructions very carefully.
 The product is for multiple use in one patient only.
OVERDOSAGE
The maximum generally recommended dosage should not be exceeded due to the potential
risk of side effects.
Acute overdosage could lead initially to hypoglycaemia and subsequently to hyperglycaemia.
Changes in glucose levels have been detected biochemically, but without clinical signs of
hypoglycaemia. Long-term overdosage could result in signs and symptoms consistent with
the known effects of human growth hormone excess.
PRESENTATIONS AND STORAGE CONDITIONS
Norditropin is available in the following presentations:
Norditropin® SimpleXx®
 Somatropin 5 mg, 10 mg or 15 mg solution for s.c. injection 1.5 mL contained in a
colourless glass cartridge
 Inactive ingredients: mannitol, histidine, poloxamer, phenol and water for injections
 The cartridge contains a rubber plunger and is closed with a rubber closure
 The cartridge is contained in a blister pack in a carton.
Norditropin® FlexPro®
 A multi-dose, disposable, pre-filled pen, consisting of somatropin 5 mg, 10 mg or 15 mg
solution for s.c. injection 1.5 mL contained in a colourless glass cartridge, permanently
sealed in a pen-injector.
 The push button, pen cap and cartridge holder on the pen-injector is colour coded
according to strength: 5 mg/1.5 mL (yellow), 10 mg/1.5 mL (blue) and 15 mg/1.5 mL
(green)
 Inactive ingredients: mannitol, histidine, poloxamer, phenol and water for injections
 The cartridge contains a rubber plunger and is closed with a rubber closure
 The pre-filled pen is packed in a carton.
Storage conditions
 Before use: Store in a refrigerator (2°C-8°C) in the outer carton, in order to protect from
light. Do not freeze.
 When in use, the product may be stored for a maximum of 28 days in a refrigerator (2C8C), alternatively stored for a maximum of 21 days below 25°C. Do not freeze.
 Norditropin retains its biological potency until the date of expiry indicated on the label.
NAME AND ADDRESS OF THE SPONSOR
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Novo Nordisk Pharmaceuticals Pty. Ltd.
Level 3, 21 Solent Circuit,
Baulkham Hills NSW 2153
POISON SCHEDULE OF THE MEDICINE
S4
DATE OF FIRST INCLUSION IN
THERAPEUTIC GOODS (THE ARTG)
THE
AUSTRALIAN
REGISTER
OF
17 January 2001 (Norditropin SimpleXx 5 mg, 10 mg, 15 mg presentations)
9 May 2011 (Norditropin FlexPro 5 mg, 10 mg, 15 mg presentations)
DATE OF MOST RECENT AMENDMENT
10 February 2016
Norditropin®, NordiPen®, SimpleXx® and FlexPro® are registered trademarks owned by
Novo Nordisk Healthcare AG. NovoFine® is a registered trademark owned by Novo Nordisk
A/S.

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